Novartis Discontinues Development of mavoglurant (AFQ056) for Fragile X Syndrome

Novartis Clinical Trials in Fragile X Ended

Novartis has announced that the company will be discontinuing its development program in Fragile X for its lead mGluR5 antagonist, mavoglurant (AFQ056), following negative results in a large international clinical trial in adults (reported in the Fall of 2013) and most recently, in a trial in adolescents. In both placebo-controlled trials, patients taking mavoglurant did not show improvement over placebo in any outcome measures.

Novartis has also announced that the current open-label extension phase of the trial will be closed, but patients will be allowed to continue on the medication until their next scheduled clinic visit, or August 29, whichever comes first. No more of the drug will be dispensed to trial participants, but mavoglurant which has already been dispensed will not be recalled.

Trial Success Probabilities - some "back of the envelope" calculations
Clinical Trial Success Probabilities – some “back of the envelope” calculations, optimistically assuming an 80% chance of making a correct choice at each step
by Mark Bear, PhD
Picower Professor of Neuroscience, MIT

We at FRAXA are disappointed by the negative results, but wish to thank Novartis for conducting superb clinical trials (at great expense to the company). It is especially disappointing that a therapeutic strategy which showed such promise in preclinical studies did not translate to a broadly effective treatment in Fragile X patients. Nevertheless, many families have experienced wonderful effects during the course of these clinical trials, and the discontinuation of the Novartis program will be difficult for them.

We hope that we, and the greater Fragile X community, can learn from these trials both about why this drug was not effective overall in patients as well as about any issues with study design and outcome measures. Such information will be useful with future trials with other therapies for Fragile X. The fact that these particular trials did not succeed does not settle the question of whether the drug modifies Fragile X syndrome and does not rule out the validity of the mGluR5 theory.

FRAXA is planning a special “Science Update” teleconference on Wednesday April 30th, at 10:30am EDT, to discuss the implications of this latest news, as well as to discuss strategy and new initiatives.  Details and call-in info


 

Letter from Novartis CEO, Dr. Joe Jiminez, to a family, shared with permission 

Date: April 24, 2014
Subject: RE: Novartis trial AFQ 056 showing real world results

Dear Dr. ___,

Thank you for your email, and for sharing your family’s very moving story about your experience on the AFQ056 trial.

First, let me share how touched and delighted I was to hear of Garrett’s progress in recent months. It’s great to hear of the progress he’s made at school and in his extra-curricular activities. As the father of three, I can imagine how proud you must feel.

I hear your concerns about the results of the unblinded data, in the face of your own personal experience and that of other parents you have spoken to. We too have heard several stories like this, and therefore I assure you that our decision to stop the ongoing development of the compound in Fragile X, which you may have seen announced today, was an extremely careful and considered one.

We took this decision in the face of the clinical evidence. Neither of the two Phase IIb/III studies in adults and adolescents met their primary endpoints. There were dramatic positive improvements in many patients in the trial, but those on AFQ056 did no better than those in the placebo arm. Many patients on placebo showed dramatic improvements during the course of the trial, which emphasizes the importance of continuous and sustained behavioral interventions in improving the long-term outcome of patients with such conditions.

Given the stories provided by many during the trial (while still blinded), we used additional qualitative scales to assess domains not captured by the primary endpoint, including communication, functional, cognitive and academic skills, such as the ones you mention improved in Garrett. In these areas too, AFQ conferred no benefits versus placebo.

I understand, as do all of my colleagues who have been deeply involved in the discovery and development of this compound, that this news will be disheartening to you and to other individuals, families and caregivers affected by Fragile X. I wish that we had had the success that this treatment for Fragile X had given us all hope for.

Kind regards
Joe


the following information was provided by Novartis

Key Points

  • The Phase IIb/III studies with mavoglurant (AFQ056) in adolescents (CAFQ056B2214) and in adults (CAFQ056A2212) with FXS, did not meet the primary endpoint of showing significant improvement in abnormal behaviors in adults and adolescents with FXS compared to placebo.
  • Mavoglurant was generally well tolerated and no safety concerns were identified in the studies.
  • Novartis regrets to confirm that it will no longer be continuing development of mavoglurant in FXS. This decision was not taken lightly, and was based on the two phase II/III trials not meeting their primary and secondary endpoints.
  • The studies were high quality with robust methodology and sufficient number of patients included (over 300 patients were randomized across the two studies).
  • Novartis would like to acknowledge the collaborative efforts of the broader Fragile X community in the mavoglurant clinical study program in FXS. Importantly, the scientific community has gained important knowledge from the AFQ clinical trial program in FXS – including learnings about the science, the disease and how to conduct clinical trials of this magnitude in these rare patient populations.

 

 Questions & Answers

  1. Why is Novartis stopping the mavoglurant development program?
    • The decision to discontinue the development program for mavoglurant in FXS was not taken lightly and was based on the two Phase IIb/III studies not meeting their primary and secondary endpoints.

 

  1. What were the results of the Phase IIb/III studies of mavoglurant (AFQ056) in adolescents and in adults with FXS?
    • Two Phase IIb/III studies with mavoglurant (AFQ056) – CAFQ056B2214 in adolescents with FXS and CAFQ056A2212 in adults with FXS  – did not meet the primary endpoint of showing significant improvement in abnormal behaviors in adults and adolescents with FXS compared to placebo.
    • Mavoglurant was generally well tolerated and no safety concerns were identified in the studies.

 

  1. What is the status of the mavoglurant extension studies in Fragile X Syndrome?
    • In view of the decision to no longer continue the development program for mavoglurant in FXS, the long-term extension studies of mavoglurant in Fragile X Syndrome will not be continuing.
    • All extension studies will be discontinued before the end of August 2014.
    • We understand that this news will be very disheartening for those involved in the management of FXS and for the individuals, families and caregivers affected by FXS.

 

  1. Will mavoglurant be available for compassionate use in FXS?
    • Per health authorities’ regulations, Novartis is not in a position to submit a request to health authorities for compassionate use for mavoglurant in FXS. We regret therefore that mavoglurant cannot be considered for compassionate use for the treatment of FXS.
    • We understand that this news will be very disheartening for those involved in the management of FXS and for the individuals, families and caregivers affected by FXS.

 

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